This Program grant reflects a conceptually and technically intertwined series of experiments to understand the biology of cell signaling and to elucidate the molecular events by which perturbations in signaling pathways may lead to the conversion of a normal cell to the malignant phenotype. The observation that the malignant phenotype is stably inherited, has lead to the identification of a vast array of genes involved in cell signaling whose altered expression leads to cellular transformation. New technologies in molecular biology and genetics, the ability to generate mice with mutations in specific proto-oncogenes, as well as the generation of transgenic mice aberrantly expressing these genes, now permits an analysis of the function of these genetic elements at an organismic level. This has provided new and significant insight into the role of these genes in normal development, and the way in which alteration in their function may lead to malignant transformation. As such, the proposals in this program rely heavily on the genetic manipulation of mice involving either gene targeting by homologous recombination or the generation of transgenic mice.